Dyslipidemias are characterized by abnormal concentrations of circulating lipids, increasing the risk of atherosclerosis and other serious conditions. Specific classes of dyslipidemias include elevated very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels, hypercholesterolemia, hypertriglyceridemia, and low concentrations of high-density lipoprotein (HDL).
Dyslipidemias are typically asymptomatic and are frequently detected during routine screening. Occasionally, xanthelasmas and xanthomas are present. These are fatty deposits under the skin surface commonly found in patients with genetic disorders such as familial hypercholesterolemia.
Saturated fats are mainly found in animal products, such as meat and dairy products (e.g., milk, cheese, butter, and yogurt), as well as in tropical oils (palm, palm kernel, and coconut).
High total and LDL cholesterol concentrations and low HDL cholesterol concentrations predict cardiovascular risk in both men and women. High triglyceride concentrations (> 150 mg/dL) are also associated with increased risk, particularly for women. Every 1% rise in total cholesterol concentration is associated with roughly a 2% increase in cardiovascular disease risk.
Although dyslipidemias are a frequent finding in all demographic groups that follow Western diets, they occur somewhat more commonly in men. Additional risk factors may include:
Diets high in total fat, saturated fat, and cholesterol (see Nutritional Considerations below).
Smoking. Cigarette smoking lowers HDL levels and is an independent risk factor for cardiovascular disease.
Obesity. Obesity is a ssociated with increased total cholesterol, LDL, VLDL, and triglycerides, as well as with decreased levels of HDL.
Diabetes mellitus and the metabolic syndrome. Hyperinsulinemia is associated with low HDL levels and hypertriglyceridemia.
Physical inactivity. A lack of regular exercise is associated with low HDL concentrations.
Nephrotic syndrome. This condition is usually associated with elevated cholesterol and triglyceride concentrations. Decreased vascular oncotic pressure due to proteinuria leads to increased lipoprotein production by the liver.
Chronic kidney disease. H ypertriglyceridemia is common.
Hypothyroidism. Total and LDL concentrations may be elevated.
Alcoholism. While moderate intake may increase HDL levels, more than moderate use leads to hypertriglyceridemia and may contribute to hypertension.
Family history. Genetic conditions, such as familial hypercholesterolemia, may contribute to dyslipidemias.
Drugs. Estrogen-progestin contraceptives, oral estrogens, tamoxifen, beta-blockers, thiazide diuretics, atypical antipsychotics, and corticosteroids may raise triglyceride levels. Protease inhibitors and other drugs may also adversely affect lipid profiles.
Pregnancy. Triglyceride concentrations may increase.
There is still debate about who should be screened for lipid disorders and at what age. The presence of risk factors, such as diabetes and obesity, should be taken into consideration when deciding who and when to screen. Ideally, the patient should be in a steady state at the time of screening, free of significant weight change and acute illness. Medications should be noted, since some drugs may interfere with lipid metabolism. Improvement of the conditions listed above that lead to hyperlipidemia may also improve the lipid profile. Hypothyroidism, chronic kidney disease, and insulin resistance should be considered in the diagnostic evaluation, as they may contribute to secondary dyslipidemia.
Patients should fast for about 12 hours before blood sampling, because chylomicron clearance can take up to 10 hours. However, a fasting sample is not required for routine cholesterol (without hypertriglyceridemia) screening.
Common laboratory assays measure total plasma cholesterol, HDL, and triglycerides directly. VLDL cholesterol levels are calculated by dividing the triglyceride value by 5. LDL cholesterol is calculated by subtracting HDL cholesterol and VLDL cholesterol from total cholesterol. When triglycerides are above 400 mg/dL, LDL calculation is inaccurate, and LDL must be measured directly.
Total cholesterol. According to NCEP guidelines, total cholesterol concentrations below 200 mg/dL are desirable. A borderline high concentration is 200 to 239 mg/ dL, and hypercholesterolemia is defined as greater than 240 mg/dL. However, epidemiologic evidence suggests that stricter standards may be appropriate. Risk of cardiac events decreases as total cholesterol levels fall until plateauing at a total cholesterol of approximately 150 mg/dL. For children, total cholesterol should be less than 180 mg/dL.
Triglyceride. Normal triglyceride concentration is less than 150 mg/dL. Borderline is 150 to 199 mg/dL, and high is 200 to 499 mg/dL. A meta-analysis of 26 studies including over 96,000 individuals showed that those in the top 20% for triglyceride concentrations had an 80% higher risk for fatal or nonfatal coronary heart disease (CHD) when compared with those in the lowest quintile.
HDL cholesterol. Concentrations of 60 mg/dL or higher are optimal. In general, an HDL concentration below 40 mg/dL is considered a major risk factor for coronary heart disease (CHD), although women’s risk of CHD increases marginally with HDL cholesterol < 50. However, HDL is often interpreted in the context of total cholesterol and LDL concentrations and may be less significant when LDL is low or when the ratio of total cholesterol to HDL, or LDL to HDL, is favorable.
LDL cholesterol. According to the NCEP, LDL cholesterol concentrations below 100 mg/dL are considered optimal. A range of 100 to 129 mg/dL is near optimal. Borderline is 130 to 159 mg/dL. High is 160 to 189 mg/dL. However, increasing evidence supports stricter standards, including reductions below 70 mg/dL for very high-risk patients. Studies of hunter-gatherer populations and normal neonates have modified the concept of “normal” cholesterol levels. Normal human LDL cholesterol concentration may be as low as 50 to 70 mg/dL, approximately half the US adult population mean. Coronary heart disease risk decreases as LDL cholesterol concentration decreases, reaching a nadir at approximately 40 mg/dL.
The mainstay of treatment for hyperlipidemia is dietary and lifestyle modification, followed by drug therapy, as necessary. Hyperlipidemia should not be considered refractory to dietary treatment if the therapeutic regimen includes animal products or more than minimal amounts of vegetable oils. Such diets do not lower LDL cholesterol concentrations as effectively as high-fiber, low-fat diets that exclude animal products (see Nutritional Considerations below).
Regular exercise can improve lipid concentrations. Low to moderate amounts of physical activity, such as walking, lower triglyceride concentrations by an average of 10 mg/dL, while raising HDL by 5 mg/dL (these numbers are means drawn from large groups). More strenuous activity may have greater effects.
Patients with familial hypercholesterolemia typically require medication starting in early childhood.
HMG CoA reductase inhibitors (statins) decrease cholesterol production in the liver and are first-line agents in the treatment of elevated LDL cholesterol. Statins also have important effects on cardiovascular risk aside from their ability to reduce lipid concentrations, and they may be indicated for high-risk patients even when lipid targets can be achieved without drug therapy. The 2013 ACC/AHA Blood Cholesterol Guideline recommends initiating statin therapy for patients with clinical atherosclerotic cardiovascular disease (ASCVD), patients with primary elevation of LDL-C ≥ 190 mg/dL, patients 40-75 years of age with diabetes and LDL-C of 70-189 mg/dL without clinical ASCVD, and patients without clinical ASCVD or diabetes who are 40-75 years old with LDL-C concentrations of 70-189 mg/dL and have an estimated 10-year ASCVD risk of ≥ 7.5%. Statins are generally well tolerated. However, they do have side effects, including myopathy and hepatotoxicity, which are well known. Several studies have also shown that statins increase the risk of developing diabetes. A recent meta-analysis of 20 studies found that individuals taking statins had a 44% increased risk for developing diabetes, compared with those not taking the cholesterol-lowering drugs. The risk appears to increase with longer use and higher dosages. Statins can cause mild weight gain and, in rare cases, memory loss that can be severe and mistaken for Alzheimer’s disease or other forms of dementia, and remit with discontinuation of the statin.
When statin therapy is insufficient, the addition of other medications may further reduce LDL concentrations. It is not clear that this leads to improvements in clinical outcomes.
Statins that are hepatically metabolized are contraindicated in patients with active liver disease, but renally metabolized statin may still be used if necessary (pravastatin). Statins are also contraindicated in pregnant or nursing women, and in those with hypersensitivity to any of the components in the medication.
Bile acid sequestrants (e.g., cholestyramine, colestipol, colesevelam) are second-line agents for LDL reduction. They inhibit bile acid resorption from the intestine and further reduce plasma LDL through other mechanisms. They can produce gastrointestinal distress, constipation, and impaired absorption of other drugs.
Fibrates (e.g., gemfibrozil, fenofibrate) are first-line treatments for elevated triglyceride concentrations and may be prescribed in combination with the above drug classes. They also raise HDL concentrations. Gallstones, dyspepsia, and myopathy may occur. Myopathy risk may be particularly high when fibrates are combined with statins.
Nicotinic acid (niacin) is a second-line therapy for all lipid disorders. Niacin is often combined with statins, as it raises HDL levels at low doses. LDL lowering occurs at higher doses, which unfortunately often causes side effects, including skin itching or burning. GI distress, flushing, hepatotoxicity, hyperglycemia, hyperuricemia, and gout may also occur.
Ezetimibe decreases GI cholesterol absorption and is a favored second-line therapy (followed by colesevelam) due to effectiveness, safety, and relative rarity of side effects. It lowers LDL and is particularly effective when combined with statins. In combination, lipid targets may be met with lower statin doses, and Framingham Risk Scores may be decreased more than typically occurs with statin therapy alone, but clinical outcomes comparing statin monotherapy with combined ezetimibe therapy are not well characterized.
Proprotein Convertase Subtilisin 9 Inhibitors (PSK-9 Inhibitors) (e.g. evolocumab, alirocumab) are the newest agents, available in injectable form, approved in 2015 to treat hyperlipidemia. These agents help to attenuate the breakdown of LDL receptors, making more LDL receptors available to bind to circulating LDL particles. In a large clinical trial, use of evolocumab not only decreased LDL as compared to standard therapy, but also decreased overall cardiovascular events. Currently, PSK-9 inhibitor use is indicated for patients with familial hypercholesterolemia or those with clinical atherosclerotic cardiac disease who require additional lowering of LDL (in addition to optimal statin therapy).
Elevated concentrations of blood lipids, particularly LDL cholesterol, are a significant risk factor for atherosclerosis and coronary heart disease (see Coronary Heart Disease chapter). Although dyslipidemia is commonly addressed with statins, it is important for patients to understand that lipid abnormalities are not caused by a “statin deficiency.” Rather, they are usually the result of dietary factors, particularly the inclusion of dairy products, meat, eggs, and hydrogenated oils and the absence of soluble fiber in the diet. Dietary factors that influence blood lipids will be described below.
Animal-Derived Food Products. Dairy products, meat, and eggs contain both saturated fat and cholesterol. Saturated fat in the diet increases LDL cholesterol concentrations. Dairy products are the leading source in Western diets, followed by meats. Red meat, chicken, and fish all contain significant amounts of saturated fat.
Dietary cholesterol is found in foods of animal origin, especially eggs. Although there has been some controversy in the lay press regarding the effects of dietary cholesterol, it is clear that dietary cholesterol influences blood cholesterol concentrations, albeit to a lesser degree than saturated fat. Roughly half of dietary cholesterol is absorbed into the bloodstream, with some variation from person to person. The greatest effects on blood cholesterol are seen when products containing cholesterol (e.g., an egg) are added to a diet that previously included little or no cholesterol; a significant increase in blood cholesterol levels is typically observed. When individuals are already consuming large amounts of saturated fat and cholesterol, additional cholesterol has a less perceptible effect, leading some to mistakenly conclude that dietary cholesterol was innocuous.
Avoidance of even fat-reduced sources of dairy products is helpful for control of lipid concentrations, given that these cause small but significant increases in LDL.
Palm oil and coconut oil. Palm and coconut are high in saturated fat and, despite intense commercial promotion of these products, their effect on blood lipids is similar to that of animal-derived saturated fat. ,
Partially hydrogenated oils (trans fats). Partially hydrogenated oils increase LDL cholesterol. Found in fried fast foods, stick margarines, and in many processed foods, these products have a linear relationship with LDL levels at intakes above approximately 3% of calorie intake.
Unfiltered coffee. Regular coffee intake is associated with an increase of 8 mg/dL in total cholesterol, a 5.4 mg/dL increase in LDL, and a 12.6 mg/dL increase in triglyceride levels, and unfiltered coffee is responsible for these effects to a greater extent than filtered coffee. Tea does not appear to have this effect. Higher compared with lower intakes of green tea are associated with a more than 5 mg/dL lower total and LDL cholesterol level, while regular consumers of black tea enjoy reductions in LDL of close to 5 mg/dL, with no effect on total or HDL cholesterol levels.
Vegetables, fruits, grains, and legumes. Most foods from plant sources are extremely low in saturated fat and contain no cholesterol. In addition, beans and other legumes, oats, barley, and many fruits and vegetables are rich in s oluble fiber, which reduces cholesterol concentrations through fecal bile excretion, reducing insulin-mediated hepatic cholesterol synthesis, and inhibition of cholesterol synthesis by fermentation products of soluble fiber. A meta-analysis of diet studies that included > 3 g/d of oat fiber found reductions in total and LDL cholesterol of roughly 12 mg/dL and 10 mg/dL, respectively.
Soy products. Soy products are often used to displace meat, dairy, or eggs from the diet and, in so doing, they help reduce the intake of saturated fat and cholesterol. However, soy isoflavones also have inhibitory effects on cholesterol synthesis, and the fiber content of soy foods promotes cholesterol excretion. Clinical trials have demonstrated that individuals eating soy products (soy milk, soy nuts) have LDL reductions of up to 11 mg/dL and total cholesterol reductions of approximately 7.5%.
Plant sterols and stanols. Food sources of plant sterols include vegetable oils, nuts, seeds, and grains, as well as certain margarines (e.g., Benecol and Take Control). Although current intakes range from 160 mg/d to 400 mg/d, these were as high as 1,000 mg/d earlier in human history. Individuals consuming vegetarian diets can double their intake when compared with omnivores. In clinical trials, these have been found to reduce LDL by between 10% and 16% and to lower triglycerides by 0.8% to 28%.
Nuts (almonds, peanuts, pecans, and walnuts) are high in fat, although their fat is typically much lower in saturated fat, compared with dairy products or meats. Nuts may have hypolipidemic effects, apparently due to their fiber or plant sterol content. A dose-response meta-analysis concluded that for every daily (1 oz) serving of nuts, total and LDL cholesterol are lowered by roughly 5%. However, nuts are high in fat and can impede efforts to lose weight if not compensated for by reducing calories from other sources.
Vegetable Oils. Some authorities recommend replacing fats that contain saturated or trans fatty acids with those richer in monounsaturated and polyunsaturated fats. In omnivorous populations, replacing saturated fat with unsaturated fat has been shown to reduce LDL significantly. However, all oils are mixtures containing varying amounts of saturated fat. For example, olive oil is approximately 13% saturated fat. In addition, all fats are energy dense (9 kcals per gram) and can promote weight gain. Studies of heart disease reversal have avoided the use of added oils.
The effects of individual foods combine into dietary patterns, which have been studied for their effects on blood lipid concentrations.
Plant-based dietary patterns. Vegetarian, especially vegan, diets have been found superior to other types of diets for lowering total and LDL cholesterol, which is understandable given that plant-based diets contain no animal fat or cholesterol and are often rich in soluble fiber. A systematic review and meta-analysis found a difference of 14 mg/dL (0.36 mmol/L) difference for total cholesterol and a 13 mg/dL (0.34 mmol/L) difference for LDL cholesterol when comparing these with control diets.
A “portfolio” combining the effects of a vegan diet, soluble fiber, soy protein, nuts, and plant sterols has been shown to lower LDL by nearly 30% in 4 weeks.
Similarly, a DASH-style diet has been found to reduce total and LDL cholesterol by 14 mg/dL and 11 mg/dL, respectively. Mediterranean diets were found to lower total cholesterol by about 9 mg/dL.
Diet changes can foster weight loss, which is helpful for improving blood lipid concentrations. This has been particularly true for plant-based diets. On average, every kg of weight loss decreases LDL and triglyceride levels by roughly 1 mg/dL each.
Diet influences HDL and triglyceride concentrations. Factors under study include the following:
Avoiding high-Glycemic-Index foods. The Glycemic Index is a measure of the effect of foods on blood glucose values. For example, wheat bread has a higher Glycemic Index than rye or pumpernickel. Diets favoring low-Glycemic-Index foods not only help reduce blood sugar concentrations; they have also been shown to significantly reduce triglyceride levels. Avoiding sugar-sweetened beverages has a similar benefit. Individuals consuming sugar-sweetened drinks frequently have higher triglyceride and lower HDL levels when compared to those who do not consume these or have these only occasionally. In a study in adults, each increase in the consumption of a sweetened beverage per day was associated with a roughly 13 mg/dL increase in triglycerides and a roughly 2 mg/dL decrease in HDL.
Increasing legume intake. A higher intake of legumes is associated with lower triglyceride levels, as well as lower total and LDL cholesterol.
Avoiding or limiting alcohol. Alcohol has diverse effects in lipoprotein metabolism, depending in part on the dose. Individuals consuming 1-2 drinks per day have lower serum triglycerides, but higher intakes have an adverse effect on LDL levels in older men and raise triglyceride levels.
Fish oil and DHA supplements. Fish oil and docosahexaenoic acid from algal oil have both been found to significantly lower triglycerides by roughly up to 30 mg/dL; however, LDL levels also increased significantly by roughly 9 mg/dL.
Garlic. Some reviewers have suggested that daily consumption of garlic in the form of powder, raw garlic, or garlic oil reduces total and LDL cholesterol by roughly 17 mg/dL and 9 mg/dL in hypercholesterolemic individuals when taken for more than 2 months. However, caution is advised, given that this is an area where commercial products are eager for research support and there is risk of publication bias. A large well-controlled randomized trial found no effects of garlic.
Probiotics. Probiotic supplementation in the form of either capsules or fermented milk products produced significant reductions in both total and LDL cholesterol of 6.5 and 8.5 mg/dL, respectively.
Caution with use of red yeast rice. An active metabolite of red yeast rice, called monacolin K, is identical to lovastatin. However, red yeast rice may contain citritin, a mycotoxin known to cause nephrotoxicity. Anaphylaxis, toxic hepatitis, and rhabdomyolysis have also been associated with the use of this product. Careful medical and laboratory monitoring would thereby be indicated for individuals who choose to use red yeast rice.
Diet: Vegetarian, low-fat, nondairy, high in soluble fiber. Avoid trans fats.
Nutrition consultation to advise patient in above diet and arrange follow-up.
Exercise prescription (patient-specific).
Alcohol restriction for hypertriglyceridemia.
Avoid oral contraceptives, if relevant.
Dyslipidemias are common contributors to atherosclerosis. However, cholesterol and triglyceride concentrations can be reduced through restriction of saturated fat, cholesterol, trans fatty acids, and total fat. Increasing dietary fiber, soy foods, and exercise can make these measures more effective. The patient’s family may also be at risk for lipid disorders and other cardiovascular problems. Their adoption of the same diet and lifestyle changes being made by the patient, including smoking cessation, will encourage patient adherence and improve family members’ health.